The broad objective of this proposal is to test the hypothesis that there is an association of immunologic responses with clinical responses in patients with metastatic pancreatic adenocarcinoma treated with anti-CTLA-4 (Ipilimumab) alone and in combination with vaccine. This study will assess safety, efficacy, and immune activation in these patients. An irradiated GM-CSF-gene modified allogeneic pancreatic cancer vaccine would provide shared immunodominant tumor antigens that could subsequently recruit and activate tumor specific T cells. The use of this vaccine has been shown to be safe and feasible in the adjuvant setting integrated with chemoradiation. In addition, it has been shown to induce mesothelin-specific T cells in the adjuvant setting and when combined with immune modulating doses of cyclophosphamide in the metastatic setting. One of the obstacles to an effective immune therapy is the induction of immune tolerance to cancer cells. One of the agents under development to modulate immune tolerance is an antibody to cytotoxic T lymphocyte-associated antigen-4 (CTLA-4), which is transiently upregulated on activated T cells and provides an inhibitory signal to T cells undergoing activation. It is also constitutively activated on regulatory T cells (Tregs). This proposal aims to evaluate Ipilimumab in patients with metastatic pancreatic cancer. In addition, we will build on our experience with the gene-modified pancreatic cancer vaccine by combining GM-CSF based vaccines with an antibody to CTLA-4. Patients will be enrolled in groups of 3. We will escalate the treatment through 4 stages: Ipilimumab 5mg/kg alone, Ipilimumab 5mg/kg + vaccine, Ipilimumab 10mg/kg alone, and Ipilimumab 10mg/kg + vaccine. Since previous studies have shown an association between toxicity and response, we will consider a toxicity level of <33% to be acceptable. The cohorts of the maximum dose Ipilimumab alone and Ipilimumab + vaccine for which the toxicity is <33% will be expanded in order to refine the estimates of toxicity and efficacy. A 2:1 randomization schema favoring the combination group will be used to allocate patients up to a total of 33 evaluable patients. The primary objective is to characterize the safety profile and immune responses in patients treated with Ipilimumab alone and Ipilimumab in combination with vaccine. The secondary objectives are to estimate response rate, progression-free survival, and overall survival in each of the study arms separately. PUBLIC HEALTH RELEVANCE: This proposal aims to combine Ipilimumab with a pancreatic cancer vaccine in patients with metastatic disease. Ipilimumab is an agent that may enhance the body's immune response to the vaccine and ultimately to the cancer.